Binge drinking, the subchronic over-ingestion of ethanol, is prevalent and increasingly being recognized as a public health concern. Although nonhuman studies have demonstrated that binge ethanol can produce neurotoxic consequences, little is known about the mechanism via which subchronic ethanol produces these consequences, nor are there therapeutics available to prevent such toxicity in individuals suffering from alcohol overdose. The focus of the proposed project will be on the development of an in vivo mousebased model of binge drinking-induced minimal neurotoxicity and the use of this model to examine the role of alpha7 nicotinic acetylcholine receptors (nAChRs) in modulating the neurotoxic effects of binge ethanol. The proposed model has two salient features. First, the model is a "minimal" model in which the smallest amount of ethanol over the shortest duration of time which reliably produces neurotoxic consequences will be defined. It is at this level of toxicity both where putative therapeutics should first be screened and where early markers of neurotoxicity will most easily be identified. Second, the model will utilize mice instead of rats which will allow for the use of the numerous, powerful genetic tools available in this species which will aid in elucidating the mechanisms underlying ethanol neurotoxicity and/or protective actions of screened agents. In this project we will utilize one such tool, alpha7 nAChR null mutant mice, to test the hypotheses that alpha7 nAChRs are involved in modulating the neurotoxic properties of ethanol. Our preliminary results with these mice strongly suggest a central role of cr7 nAChRs in modulating toxic properties of subchronic ethanol. These data include a demonstration that ethanol toxicity is enhanced in neuronal cultures derived from alpha7 nAChR null mutant mice and that the lethal effects of ethanol are enhanced in adult alpha7 null mutant mice. Additionally, agents selective for al nAChRs protect against ethanol-induced neurotoxicity. The successful completion of this project will not only provide a valuable animal model for studying the mechanism via which subchronic ethanol produces neurotoxic consequences, but will also advance knowledge on the role of alpha7 nAChRs in modulating these consequences. Via the latter, the development of alpha7-selective agents as therapeutics to treat binge drinking-induced neurotoxicity may be fostered.